Inhibition of adrenal phenethanolamine N-methyltransferase by substituted benzimidazoles

Mandel, L; Porter, Curt C.; Kuehl, Frederick A.; Jensen, N. P.; Schmitt, S. M.; Windholz, T. B.; Beattie, Thomas R.; Carty, Joanne; Christensen, B. G.; Shen, T. Y.

doi:10.1021/jm00300a005

Cited by 24 publications

(21 citation statements)

References 2 publications

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“…5 μM (2-aminobenzimidazole, compound 6, and 2-amino-1-methybenzimidazole, compound 7), are both based on the benzimidazole core. As discussed above, benzimidazoles have been shown previously to inhibit PNMT [32]. The third fragment hit with a benzimidazole core (5-chlorobenzimidazole, compound 9), had a 20-fold lower binding affinity (K d of 97 μM), suggesting that direct and water-mediated hydrogen bonds to the 2-amino groups of compounds 6 and 7 contribute considerably to ligand affinity for hPNMT.…”

Section: Itc Evaluation Of Fragment Hitsmentioning

confidence: 87%

“…The electron density for these three hits was excellent, and ITC measurements confirmed that all three bind to hPNMT, two of them with very high LE values. Benzimidazoles have been investigated previously as inhibitors of PNMT, although the earlier work was performed on the bovine enzyme [32]. To further characterize the interaction of benzimidazole-based fragments with the human enzyme, a series of compounds (compounds 13-17; Figure 5) closely related to the FBS-X benzimidazole hits were synthesized.…”

Section: Elaborated Benzimidazole Compoundsmentioning

confidence: 99%

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Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors

Drinkwater

Lovell

et al. 2010

Biochemical Journal

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CNS (central nervous system) adrenaline (epinephrine) is implicated in a wide range of physiological and pathological conditions. PNMT (phenylethanolamine N-methyltransferase) catalyses the final step in the biosynthesis of adrenaline, the conversion of noradrenaline (norepinephrine) to adrenaline by methylation. To help elucidate the role of CNS adrenaline, and to develop potential drug leads, potent, selective and CNS-active inhibitors are required. The fragment screening approach has advantages over other lead discovery methods including high hit rates, more efficient hits and the ability to sample chemical diversity more easily. In the present study we applied fragment-based screening approaches to the enzyme PNMT. We used crystallography as the primary screen and identified 12 hits from a small commercial library of 384 drug-like fragments. The hits include nine chemicals with two fused rings and three single-ring chemical systems. Eight of the hits come from three chemical classes: benzimidazoles (a known class of PNMT inhibitor), purines and quinolines. Nine of the hits have measurable binding affinities (~5-700 μM) as determined by isothermal titration calorimetry and all nine have ligand efficiencies of 0.39 kcal/mol per heavy atom or better (1 kcal≈4.184 kJ). We synthesized five elaborated benzimidazole compounds and characterized their binding to PNMT, showing for the first time how this class of inhibitors interact with the noradrenaline-binding site. Finally, we performed a pilot study with PNMT for fragment-based screening by MS showing that this approach could be used as a fast and efficient first-pass screening method prior to characterization of binding mode and affinity of hits.

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Section: Itc Evaluation Of Fragment Hitsmentioning

confidence: 87%

Section: Elaborated Benzimidazole Compoundsmentioning

confidence: 99%

Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors

Drinkwater

Lovell

et al. 2010

Biochemical Journal

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“…The chemical reagents used in synthesis were purchased from E. Merck, Fluka, Sigma, Acros and Aldrich. Compounds 4 [24], 6 [38], 7 [39], 10 [40], and 11 [40] were prepared according to the literature methods.…”

Section: Methodsmentioning

confidence: 99%

“…Cyclization of commercially available 4,5-dichloro-o-phenylenediamine with urea [38] and halogenation with phosphorous oxychloride in the presence of hydrochloric acid gas [39] and alkylation with cyclopentyl bromide led to the formation of 8. Compound 9 was obtained by reaction of 8 with isopropyl amine.…”

Section: Chemistrymentioning

confidence: 99%

“…Condensation of o-phenylenediamines (17, 16, 4,5-dichloro-ophenylenediamine, 2) with Na 2 S 2 O 5 adduct of appropriate substituted benzaldehydes gave the desired derivatives (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). In the last step, compounds 24-27 were put in reaction with cyclopentyl bromide to afford the corresponding alkalized derivatives (28)(29)(30)(31).…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and in vitro antimicrobial activity of some novel substituted benzimidazole derivatives having potent activity against MRSA

Tunçbìlek

Kiper²,

Altanlar

2009

European Journal of Medicinal Chemistry

119

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ChemInform Abstract: DIE INHIBIERUNG DER ADRENAL‐PHENAETHANOLAMIN‐N‐METHYLTRANSFERASE DURCH SUBSTITUIERTE BENZIMIDAZOLE

Mandel¹,

Porter²,

Kuehl³

et al. 1971

Chemischer Informationsdienst. Organische Chemie

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Inhibition of adrenal phenethanolamine N-methyltransferase by substituted benzimidazoles

Cited by 24 publications

References 2 publications

Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors

Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors

Synthesis and in vitro antimicrobial activity of some novel substituted benzimidazole derivatives having potent activity against MRSA

ChemInform Abstract: DIE INHIBIERUNG DER ADRENAL‐PHENAETHANOLAMIN‐N‐METHYLTRANSFERASE DURCH SUBSTITUIERTE BENZIMIDAZOLE

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